FR2933982A1 - NOVEL IMIDAZO-1,2-A! PYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE IN PARTICULAR AS MET INHIBITORS - Google Patents

Abstract

The invention relates to new products of formula (I): ## EQU1 ## in which: Ra represents H, Hal, aryl or optionally substituted heteroaryl; Rb is H, Rc, -COORc, -CO-Rc or -CO-NRcRd; with Rc is alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, all optionally substituted; Rd is H, alk or cycloalkyl; these products being in all isomeric forms and salts, as medicaments especially as MET inhibitors.

Description

NOVEL IMIDAZO [1,2-a] PYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE, IN PARTICULAR AS MET INHIBITORS The present invention relates to novel imidazo [1,2-a] pyrimidine derivatives , the process for their preparation, the novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use of such imidazo [1,2-a] pyrimidine derivatives. The present invention relates more particularly to novel imidazo [1,2-a] pyrimidine derivatives having anticancer activity, via the modulation of the activity of proteins, in particular kinases. To date, most of the commercial compounds used in chemotherapy are cytotoxic drugs that pose significant problems of side effects and tolerance by patients. These effects could be limited insofar as the drugs used act selectively on cancer cells, excluding healthy cells. One of the solutions to limit the undesirable effects of chemotherapy may therefore consist of the use of drugs acting on metabolic pathways or constitutive elements of these pathways, mainly expressed in cancer cells, and which would be little or no expression in healthy cells. Protein kinase is a family of enzymes that catalyze the phosphorylation of hydroxy groups of protein-specific residues such as tyrosine, serine or threonine residues. Such phosphorylations can greatly alter the function of proteins: thus, protein kinases play an important role in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell adhesion and motility, Cell differentiation or cell survival, with some protein kinases playing a central role in the initiation, development, and completion of cell cycle events.

Among the various cellular functions in which the activity of a protein kinase is involved, some processes represent attractive targets for treating certain diseases. Examples include angiogenesis and cell cycle control as well as cell proliferation, in which protein kinases can play a critical role. These processes are particularly essential for the growth of solid tumors as well as other diseases: in particular inhibitory molecules of such kinases are able to limit unwanted cell proliferations such as those observed in cancers, and may intervene in the prevention, control and treatment of cancer. regulation or treatment of neurodegenerative diseases such as Alzheimer's disease or neuronal apoptosis. The present invention relates to novel derivatives with inhibitory effects vis-à-vis protein kinases. The products according to the present invention can thus notably be used for the prevention or the treatment of diseases that can be modulated by the inhibition of protein kinases. The products according to the present invention exhibit in particular an anticancer activity, via the modulation of the activity of kinases. Of the kinases for which modulation of activity is desired, MET as well as MET protein mutants are preferred. The present invention also relates to the use of said derivatives for the preparation of a medicament for the treatment of humans.

Thus, one of the objects of the present invention is to provide compositions having an anticancer activity, acting in particular vis-à-vis kinases. Of the kinases for which modulation of activity is desired, MET is preferred.

In the pharmacological part below, it is shown in biochemical tests and on cell lines that the products of the present application thus inhibit, in particular, the autophosphorylation activity of MET and the proliferation of cells whose growth depends on MET. or its mutant forms.

MET, or Hepatocyte Growth Factor Receptor, is a receptor with tyrosine kinase activity expressed in particular by epithelial and endothelial cells. HGF, Hepatocyte Growth Factor, is described as the specific ligand of MET. HGF is secreted by the mesenchymal cells and activates the MET receptor that moderates. As a consequence, the receptor autophosphorylates on tyrosines of catalytic domain Y1230, Y1234 and Y1235. MET stimulation by HGF induces proliferation, scattering (or dispersion), cell motility, resistance to apoptosis, invasion and angiogenesis.

MET, like HGF, are found to be overexpressed in many human tumors and a wide variety of cancers. MET is also found amplified in gastric tumors and glioblastomas. Numerous point mutations of the MET gene have also been described in tumors, in particular in the kinase domain, but also in the juxtamembrane domain and the SEMA domain. Overexpression, amplification or mutations cause constitutive activation of the receptor and deregulation of its functions. The present invention thus relates in particular to new inhibitors of the MET protein kinase and its mutants, which can be used for anti-proliferative and anti-metastatic treatment, especially in oncology.

The present invention also relates to novel inhibitors of the MET protein kinase and its mutants, which can be used for anti-angiogenic treatment, in particular in oncology. The subject of the present invention is the products of formula (I): in which: Ra represents a hydrogen atom, a halogen atom, an aryl radical, or a heteroaryl radical, these aryl and heteroaryl radicals being optionally substituted as indicated below; Rb represents a hydrogen atom, a radical Rc, -COORc, -CO-Rc or a radical -CONRcRd; with Rc represents an alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl radical, all these radicals being optionally substituted as indicated below; moreover, when Rc represents cycloalkyl, then this cycloalkyl radical is optionally substituted by one or more radicals selected from heterocycloalkyl, aryl and heteroaryl themselves optionally substituted as indicated below; moreover, when Rc represents alkyl, then this alkyl radical is optionally substituted by one or more heterocycloalkyls, themselves optionally substituted as indicated below; Rd represents a hydrogen atom or an alkyl or cycloalkyl radical; all the radicals defined above, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, being optionally substituted with one or more radicals chosen from halogen atoms, and hydroxyl, alkoxy, CN, CF3, -NR1 R2, -OOH radicals; , -COOalk, -00NR1 R2 and - NRI COR2; the alkyl radicals being additionally optionally substituted by an aryl or heteroaryl radical, themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy and NR3R4 radicals; cycloalkyl, heterocycloalkyl radicals; aryl or heteroaryl being further optionally substituted by an alkyl radical itself optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy and NR3R4 radicals; NR1 R2 being such that: either, R1 and R2 being identical or different, one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a radical cycloalkyl or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including 1 any NH it contains being optionally substituted; NR3R4 being such that: either, R3 and R4 being identical or different, one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a cycloalkyl radical; or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heterocycloalkyl, heteroaryl or phenyl radicals, themselves optionally substituted, or R 3 and R 4 form, with the nitrogen atom to which they are bonded, a radical cyclic ring containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the cyclic radicals that can be formed by R 1 and R 2 or R 3 and R 4 respectively with the nitrogen atom to which they are bonded, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, oxo radicals, alkoxy, NH2; NHalk, N (alk) 2, and the alkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter radicals the alkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals selected from the group consisting of halogen and hydroxyl, alkyl and alkoxy radicals having 1 to 4 carbon atoms, NH 2; NHalk and N (alk) 2; R 1 and R 2 are identical or different having the meanings indicated above, all the above alkyl (alk) and alkoxy radicals containing from 1 to 6 carbon atoms, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The subject of the present invention is the products of formula (I) as defined above in which: Ra represents a hydrogen atom; a halogen atom; or an aryl or heteroaryl radical, these aryl and heteroaryl radicals being optionally substituted as indicated below; Rb represents a hydrogen atom, a -CO-Rc radical or a -CONRcRd radical; with Rc represents an alkyl radical or a cycloalkyl radical, both optionally substituted with one or more radicals chosen from hydroxyl, alkoxy, NR1 R2, heterocycloalkyl, aryl and heteroaryl radicals themselves optionally substituted as indicated below; Rd represents a hydrogen atom or an alkyl radical; all the radicals defined above, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, being optionally substituted by one or more radicals chosen from halogen atoms, and hydroxyl, alkoxy, -NR 1 R 2, -OOOH, -COOalk radicals; and -CONR1 R2, NR1 R2 being such that: either, R1 and R2 being identical or different, one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom; hydrogen, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including 1 any NH it contains being optionally substituted; NR3R4 being such that: either, R3 and R4 being identical or different, one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a cycloalkyl radical; or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heterocycloalkyl, heteroaryl or phenyl radicals, themselves optionally substituted, or R 3 and R 4 form, with the nitrogen atom to which they are bonded, a radical cyclic ring containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the cyclic radicals that can be formed by R 1 and R 2 or R 3 and R 4 respectively with the nitrogen atom to which they are bonded, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, alkoxy radicals; and the alkyl, phenyl and CH 2 -phenyl radicals, in which the alkyl or phenyl radicals are themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals. NH2, NHalk and N (alk) 2; all the above-mentioned alkyl (alk) or alkoxy radicals containing from 1 to 6 carbon atoms, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or below, in which: Ra represents a hydrogen atom; a halogen atom; or an optionally substituted phenyl radical as indicated below; Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-N radical RcRd; with Rc represents an alkyl or cycloalkyl radical, both optionally substituted by one or more radicals chosen from hydroxyl, alkoxy, NR1R2 and phenyl radicals, itself optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl radicals; alkoxy, alkyl, NH2, NHalk and N (alk) 2; Rd represents a hydrogen atom or an alkyl radical; NR1 R2 is such that either, R1 and R2 being identical or different, one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical; or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4 or phenyl radicals, themselves optionally substituted; or R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 4 to 7 members and optionally another heteroatom selected from O, S, N and NH, this radical including the optional NH that it contains being optionally substituted; NR3R4 being such that either R3 and R4 are identical or different, represent a hydrogen atom or an alkyl radical optionally substituted by one or more identical or different radicals chosen from hydroxyl or alkoxy radicals, or R3 and R4 form with the atom of nitrogen to which they are attached a cyclic radical containing from 4 to 7 members and optionally another heteroatom selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the cyclic radicals that R 1 and R 2 or R 3 and R 4 may form respectively with the nitrogen atom to which they are bonded, being optionally substituted by one or more identical or different radicals as defined above; all the above alkyl or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral acids and organic or with the inorganic and organic bases of said products of formula (I). The subject of the present invention is the products of formula (I) as defined above or below, in which: Ra represents a hydrogen atom; a halogen atom; or a phenyl radical optionally substituted with a halogen atom; Rb represents a hydrogen atom, a -CO-Rc radical or a -CONRcRd radical; with Rc represents an alkyl or cycloalkyl radical optionally substituted with one or more radicals chosen from hydroxyl, alkoxy and NR1 R2 radicals; Rd represents a hydrogen atom; NR1R2 being such that either R1 and R2, which may be identical or different, represent a hydrogen atom or an alkyl radical optionally substituted by one or more identical or different radicals chosen from hydroxyl, alkoxy and NH2 radicals; NHalk and N (alk) 2 or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 4 to 7 members and optionally another heteroatom chosen from O, S, N and NH, optionally substituted by an alkyl, phenyl or -CH 2 -phenyl radical, the latter radicals themselves being optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals. NH2, NHalk and N (alk) 2; all the above alkyl (alk) or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

In the products of formula (I) and in the following: the term alkyl radical (or alk) denotes the radicals, linear and, if appropriate, branched, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl, as well as their linear or branched positional isomers: alkyl radicals containing 1 to 6 carbon atoms and more particularly the alkyl radicals containing from 1 to 4 carbon atoms from the above list; the term "alkoxy radical" denotes the linear and, if appropriate, branched, methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy radicals, as well as their linear or branched positional isomers: alkoxy radicals containing 1 to 4 carbon atoms from the above list; the term "halogen atom" denotes the chlorine, bromine, iodine or fluorine atoms and preferably the chlorine, bromine or fluorine atom. the term "cycloalkyl radical" denotes a saturated carbocyclic radical containing 3 to 10 carbon atoms and thus particularly denotes the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, and especially the cyclopropyl, cyclopentyl and cyclohexyl radicals; the term "heterocycloalkyl radical" thus denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 members interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms; for example, morpholinyl, thiomorpholinyl, homomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, hexahydropyran, oxodihydropyridazinyl or oxetanyl radicals, all these radicals being optionally substituted; mention may in particular be made of morpholinyl, thiomorpholinyl, homomorpholinyl, piperazinyl, piperidyl, homopiperazinyl or pyrrolidinyl radicals, the terms aryl and heteroaryl denote unsaturated or partially unsaturated, respectively carbocyclic and heterocyclic, monocyclic or bicyclic radicals, containing at most 12 links, optionally containing a C (0) -group, heterocyclic radicals containing one or more identical or different heteroatoms selected from O, N, or S with N, optionally substituted; the term "aryl radical" thus denotes monocyclic or bicyclic radicals containing 6 to 12 members, such as, for example, the phenyl, naphthyl, biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly the phenyl and naphthyl radicals and even more particularly the phenyl radical. It may be noted that a carbocyclic radical containing a C (O) linkage is, for example, the tetralone radical; the term "heteroaryl radical" thus denotes monocyclic or bicyclic radicals containing 5 to 12 members: monocyclic heteroaryl radicals such as, for example, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, 3-furyl, pyrannyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl as 3- or 4-isoxazolyl, furazannyl, free or salt tetrazolyl, all these radicals being optionally substituted, among which more particularly the thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, these radicals being optionally substituted; bicyclic heteroaryl radicals such as, for example, benzothienyl radicals such as 3-benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, quinolone, tetralone, adamentyl, benzofuryl, isobenzofuryl, dihydrobenzofuran, ethylenedioxyphenyl, thianthrenyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl; azaindolyl, indazolyl, purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl or oxodihydropyridino pyrazolyl, all of these radicals being optionally substituted; As examples of heteroaryl or bicyclic radicals, there may be mentioned more particularly the pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl, benzothiazolyl or benzimidazolyl radicals optionally substituted by one or more identical or different substituents as indicated above. The carboxyl group (s) of the products of formula (I) may be salified or esterified with the various groups known to those skilled in the art, among which may be mentioned, for example: - among salification compounds, mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine among the esterification compounds, the alkyl radicals to form alkoxycarbonyl groups, such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals being substitutable; by radicals chosen from, for example, halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals such as, for example, chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl groups; or phenethyl. The addition salts with the mineral or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids. It may be recalled that the stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of the ethane derivatives. However, there is another type of stereoisomerism, due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomerism or cis-trans isomerism. The term stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above. When NR 1 R 2 or NR 3 R 4 forms a ring as defined above, such an amino ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl, homomorpholinyl, piperazinyl or homopiperazinyl radicals, these radicals themselves being optionally substituted as indicated above or hereafter: for example by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, alkoxy, phenyl and CH 2 -phenyl radicals, the alkyl or phenyl radicals being they themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals; NH 2, NHalk and N (alk) 2 The NR 1 R 2 or NR 3 R 4 ring may more particularly be chosen from pyrrolidinyl and morpholino radicals optionally substituted by one or two alkyl or piperazinyl radicals optionally substituted on the second nitrogen atom by an alkyl or phenyl radical. and CH 2 -phenyl, themselves optionally substituted with one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl and alkoxy radicals. The subject of the present invention is the products of formula (I) as defined above or below, in which: Ra represents a hydrogen atom; Rb represents a hydrogen atom, a CO-Rc radical or a radical -COûN RcRd; with Rc represents a cyclopropyl radical or an alkyl radical optionally substituted by an alkoxy radical or NR1 R2; Rd represents a hydrogen atom, NR1R2 being such that either R1 and R2 are identical or different, represent a hydrogen atom or an alkyl radical or R1 and R2 together with the nitrogen atom to which they are attached form a morpholinyl radical; the above alkyl or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral acids and organic or with the inorganic and organic bases of said products of formula (I). The subject of the present invention is particularly the products of formula (I) as defined above, corresponding to the following formulas: 6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol 2-Amine N- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6- (imidazo [1,2-a] pyrimidine 1- [6- (Imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] -1,3-benzothiazol-2-yl] acetamide -3-ylsulfanyl) -1,3-benzothiazol-2-yl] acetamide 3- [2- (morpholin-4-yl) ethyl] ure 20 as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The present invention also relates to the following products of formula (I): 1- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] -3- [2 N- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] -1-pyrrolidinepropanamide, 25 (pyrrolidin-1-yl) ethyl] urea, and the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The present invention also relates to any process for preparing the products of formula (I) as defined above.

The products according to the invention can be prepared from conventional methods of organic chemistry. Preparation of compounds of formula (I) Schemes 1 and 2 below are illustrative of the methods used for the preparation of the products of formula (I). As such, they can not constitute a limitation of the scope of the invention, as regards the methods of preparation of the claimed compounds. The products of formula (I) as defined above according to the present invention can thus be prepared in particular according to the method described in diagrams 1 and 2 below.

The present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 1 as defined below. The present invention thus also relates to the process for preparing products of formula (I) according to Scheme 2 as defined below.

Scheme 1: NH NH HS + NH 2 (A) (B) (C) H N Functionalization Cyclization In Scheme 1 above, the substituents Ra and Rb have the meanings given above.

The compounds (I) for which Ra and Rb have the same meanings can be obtained from the compounds (I) for which Rb = H. Rc-COCl NH2 Rc-CO-O-CO-Rc i N (I) Rb = H (I) Rb = CORc More particularly, the compounds (I) for which Rb = CORc (with Rc as defined above) can be obtained, for example: by reaction of an acid chloride of formula Rc-COCI in the presence, for example, of a solvent such as pyridine at a temperature in the region of 20 ° C., by reaction of an acid anhydride of formula Rc-CO-O-CO-Rc, in the presence, for example, of a solvent such as pyridine at a temperature in the region of 20 ° C., by reaction with a carboxylic acid of formula Rc-000H under the conditions, for example, described by D. DesMarteau et al., (Chem Lett, 2000, 9 , 1052) in the presence of 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and in the presence of a base such as triethylamine, at a temperature between 20 ° C and the temperature the reflux of the solvent. (1) Rb = CO-O-Rc More particularly, the compounds (I) for which Rb = CO-O-Rc (with Rc as defined above) can be obtained, for example, by reaction with a chlorocarbonate Rc- O-COX (X = Cl) on the compounds (I) for which Rb = H, in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, or in pyridine, at a temperature in the vicinity of 20 ° C. (1) Rb = H R-O-COX (D) R Rc (Rd) NH Rd i N \ Rc (I) Rb = CON (Rc) Rd More particularly, the compounds (I) for which Rb = CON (Rc) Rd (with Rc and Rd as defined above) can be obtained, for example, by reaction of carbamates (D) where R = phenyl, with amines Rc (Rd) NH (with Rc and Rd as defined above). above) in the presence of an aprotic solvent such as tetrahydrofuran, at a temperature of 20 ° C. The carbamates (D) can be obtained, for example, by reaction with a chlorocarbonate RO-COX (X = Cl) on the compounds (I) for which Rb = H, in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, or in pyridine, at a temperature in the region of 20 ° C. o \ R (E) o \ R Rc deprotection

NH (I) Rb = H (I) Rb = Rc More particularly, compounds (I) for which Rb = Rc (with Rc as defined above) can be obtained, for example: by deprotection of carbamates (E) with R = t-Butyl according to a method customary for those skilled in the art, for example with trifluoroacetic acid, in a solvent such as dichloromethane at a temperature in the region of 20 ° C from the compounds (I) for which Rb = H by the methods described in EP 0408437 or R. A Glennon et al. (Journal of Medicinal Chemistry, 1981, 24, 766-769). The carbamates (E) can be obtained, for example, by reaction of the carbamates (D) where R = t-butyl, with Rc-X halides (with Rc as defined above) in the presence of a solvent such as N, N-dimethylformamide, in the presence of a base such as sodium hydride, at a temperature of between 20 ° C. and 90 ° C. The compounds (I) for which Rb = H can be obtained by cyclization of the compounds (C) ) according to a method customary for those skilled in the art, for example by applying the methods described by H. Masaichi et al. (Journal of Medicinal Chemistry, 2007, 50 (18), 4453-4470), by reaction of potassium thiocyanate and bromine in the presence of acid such as acetic acid at a temperature between 20 ° C and the reflux temperature solvent. The compounds (C) can be obtained by hydrolysis of the acetamide function of the compounds (B) according to a method customary for those skilled in the art, for example with the aid of acid such as hydrochloric acid, in a solvent such as ethanol, at a temperature between 20 ° C and the reflux of the solvent. The compounds (B) can be obtained by coupling the compounds (A) with Ra as defined above with N- (4-sulfanylphenyl) acetamide (commercial product) under the conditions described for example by R. Varala et al. . (Chemistry Letters, 2004, 33 (12), 1614-1615), by M. Winn et al. (Journal of Medicinal Chemistry, 2001, 44, 4393-4403) in the presence of a base such as, for example, potassium carbonate in a solvent such as dimethylsulfoxide at a temperature of between 20 ° C. and the reflux temperature of the solvent. Such reactions can also be carried out under microwave irradiation. The compounds (B) can also be obtained by coupling the compounds (A) as described above with other 4-aminothiophenol derivatives such as (4-NHR) Ph-SH derivatives or the amine function is free ((4 -NH2) Ph-SH, commercial product) or protected by a t-butyloxycarbonyl group for example ((4-NHCO2tBu) Ph-SH, known product). H2N 1 NB (OH) 2 Ra-B (OH) 2 or Ra-B (OR) 2 CICH2CHO bromination H2 Ra (A2) (A) Compounds (A) are either commercial (Ra = H) or prepared by bromation of the compounds (A1), according to a method customary for those skilled in the art, for example according to the conditions described by SC Goodacre et al. (Journal of Medicinal Chemistry, 2006, 49 (1) 35-38); using bromine or N-bromosuccinimide in a solvent such as ethanol or chloroform, at a temperature between 20 ° C and the reflux of the solvent. The compounds (Al) are either commercial (Ra = H) or can be obtained according to a method customary for those skilled in the art, for example by cyclization of the 2-aminopyrimidine compounds (A2) with the choroacetaldehyde as described for example by Y Rival et al. (European Journal of Medicinal Chemistry, 1991, 26, 13-18), in the presence of a base such as sodium hydrogencarbonate, in a solvent such as ethanol at a temperature between 20 ° C and the solvent temperature.

The compounds (A2) are either commercially available or can be obtained according to a method customary for those skilled in the art, for example from 2-amino-5-halopyrimidines (commercial products) by coupling reaction with boronic acids R. B (OH) 2 or Ra-B (OR) 2 boronic esters by the methods described by Y. Gong et al. (Synlett, 2000, 6, 829-831) or M. Berlin et al. (Bioorganic & Medicinal Chemistry Letters, 2006, 16, 989-994) from 5- (2-aminopyrimidine) boronic acid (commercial product) by coupling reaction with commercial compounds Ra-X (X = I, Cl, Br) using the methods described by KM Clapham et al. (European Journal of Organic Chemistry, 2007, 34, 5712-5716). Scheme 2: Rc (Rd) NH R NH2 s (F) Rd Rd N \ (G) O Rc reduction coupling HS Rd N (H) Rc coupling i Rd N Rc (I) Rb = CONHRc

In Scheme 2 above, the substituents Ra, Rc and Rd have the meanings given above.

The compounds (I) for which Ra has the same meanings as above and for which Rb = H or Rb = CON (Rc) Rd can be obtained by coupling reaction of the compounds (A) with Ra as defined above. with the compounds (H) with Rc and Rd as defined above, as described above for the preparation of the compounds (B).

The compounds (H) for which Rc and Rd have the same meanings indicated above can be obtained for example by reducing the compounds (G) with DL-dithiotreitol, in the presence of sodium hydrogen carbonate or potassium dihydrogenphosphate in a solvent such as ethanol and at a temperature between 20 ° C and the reflux of the solvent. The compounds (G) for which Rc and Rd have the same meanings indicated above can be obtained for example from the compounds (E), as described above for the preparation of the compounds (I) with Rb = CON (Rc ) Rd.

The compounds (F) can be obtained from 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial product) as described above for the preparation of the compounds (D). Among the starting products of formulas (A), (A1), (A2), (F) and (G), some are known and can be obtained either commercially or according to the usual methods known to those skilled in the art, for example from commercial products. It is understood by those skilled in the art that, for the implementation of the processes according to the invention described above, it may be necessary to introduce protective groups of the amino, carboxyl and alcohol functions in order to avoid side reactions. The following non-exhaustive list of examples of protection of reactive functions may be mentioned: the hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl groups, the amino groups may be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl, BOC, benzyloxycarbonyl, phthalimido or other radicals known in the peptide chemistry. The acid functions may be protected for example under form of esters formed with easily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry. A list of different protective groups used in the manuals known to those skilled in the art and for example in the patent FR 2,499,995.

It may be noted that intermediate products or products of formula (I) thus obtained can be subjected, if desired and if necessary, to the processes described above, to obtain other intermediates or other products of formula (I), one or more reactions of transformations known to those skilled in the art such as for example: a) an esterification reaction of acid function, b) a saponification reaction of ester function in acid function, c) a reaction of reduction of the free or esterified carboxy function as a function of alcohol, d) a conversion reaction of alkoxy function with hydroxyl function, or even of hydroxyl function with alkoxy function, e) a reaction of elimination of the protective groups that can carry protected reactive functions, f) a salification reaction with a mineral or organic acid or a base to obtain the corresponding salt, g) a doubling reaction of the forms racemates in duplicated products, said products of formula (I) thus obtained being in all possible isomeric forms racemic, enantiomers and diastereoisomers.

The reactions a) to g) can be carried out under the usual conditions known to those skilled in the art such as, for example, those indicated below. a) The products described above may, if desired, be subjected, on the possible carboxy functions, to esterification reactions which may be carried out according to the usual methods known to those skilled in the art. b) The possible acid-functional ester function transformations of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by acid or alkaline hydrolysis, for example with sodium hydroxide or sodium hydroxide. potash in an alcoholic medium such as, for example, in methanol or in hydrochloric or sulfuric acid. The saponification reaction can be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide. c) The optional free or esterified carboxy functions of the products described above may, if desired, be reduced according to the alcohol by the methods known to those skilled in the art: the optional esterified carboxy functions may, if desired, be reduced according to alcohol by the methods known to those skilled in the art and in particular by lithium hydride and aluminum in a solvent such as for example tetrahydrofuran or dioxane or ethyl ether. The optional free carboxy functions of the products described above may, if desired, be reduced in particular alcohol function by boron hydride. d) The optional alkoxy functions, such as methoxy in particular, of the products described above may, if desired, be converted into hydroxyl function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as For example, methylene chloride, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux. e) The elimination of protective groups such as for example those indicated above can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric acid, benzene sulfonic acid or para-toluenesulphonic, formic or trifluoroacetic or catalytic hydrogenation. The phthalimido group may be removed by hydrazine. f) The products described above may, if desired, be the subject of salification reactions, for example by a mineral or organic acid or by a mineral or organic base according to the usual methods known to those skilled in the art: such salification reaction can be carried out for example in the presence of hydrochloric acid for example or tartaric acid, citric or methanesulfonic acid in an alcohol such as for example ethanol or methanol. g) The optional optically active forms of the products described above may be prepared by resolution of the racemates according to the usual methods known to those skilled in the art. The products of formula (I) as defined above, as well as their addition salts with acids, have interesting pharmacological properties, in particular because of their kinase inhibiting properties as indicated above. The products of the present invention are especially useful for tumor therapy.

The products of the invention can also increase the therapeutic effects of commonly used anti-tumor agents. These properties justify their application in therapeutics and the subject of the invention is particularly useful as medicaments, the products of formula (I) as defined above, said products of formula (I) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I).

The subject of the invention is, as medicaments, the products corresponding to the following formulas: 6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-amine N- [6- (Imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6- (imidazo [1,2-a] pyrimidine 1- [6- (Imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] -3-ylsulfanyl) -1,3-benzothiazol-2-yl] acetamide [2- (morpholin-4-yl) ethyl] urea as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). The present invention also relates to the following products of formula (I): 1- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] -3- [ 2- (Pyrrolidin-1-yl) ethyl] urea-N- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] -1-pyrrolidinpropanamide as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). The invention also relates to pharmaceutical compositions containing as active principle at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, optionally, a pharmaceutically acceptable carrier. The invention thus extends to pharmaceutical compositions containing as active principle at least one of the drugs as defined above. Such pharmaceutical compositions of the present invention may also, if appropriate, contain active principles of other antimitotic drugs such as in particular those based on taxol, cisplatin, intercalating agents of DNA and others.

These pharmaceutical compositions may be administered orally, parenterally or locally by topical application to the skin and mucous membranes or by intravenous or intramuscular injection. These compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, pills, lozenges, capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods. The active ingredient can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, the fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives.

The usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 0.05 to 5 g per day in the adult, or preferably from 0.1 to 2 g. per day. The subject of the present invention is also the use of the products of formula (I) as defined above or of pharmaceutically acceptable salts of these products for the preparation of a medicament intended for inhibiting the activity of a protein kinase. The subject of the present invention is also the use of products of formula (I) as defined above for the preparation of a medicament intended for the treatment or prevention of a disease characterized by the dysregulation of a protein kinase. Such a medicament may especially be intended for the treatment or prevention of a disease in a mammal. The present invention also relates to the use defined above wherein the protein kinase is a protein tyrosine kinase. The subject of the present invention is also the use defined above in which the protein tyrosine kinase is MET or its mutant forms. The present invention also relates to the use defined above in which the protein kinase is in a cell culture. The present invention also relates to the use defined above wherein the protein kinase is in a mammal. The present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the prevention or treatment of diseases related to uncontrolled proliferation. The present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: disorders proliferation of blood vessels, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.

The present invention thus particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of diseases in oncology and in particular for treatment of cancers. Among these cancers, one is interested in the treatment of solid or liquid tumors, in the treatment of cancers resistant to cytotoxic agents. The products of the present invention cited can in particular be used for the treatment of primary tumors and / or metastases, particularly in gastric, hepatic, renal, ovarian, colon, prostate, lung cancers (NSCLC and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid hematopoietic tumors or myeloid, in sarcomas, in cancers of the brain, larynx, lymphatic system, cancers of the bones and pancreas. The subject of the present invention is also the use of the products of formula (I) as defined above for the preparation of medicaments intended for the chemotherapy of cancers. Such drugs for cancer chemotherapy may be used alone or in combination. The products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or in combination with other therapeutic agents, for example. Such therapeutic agents may be commonly used anti-tumor agents.

As kinase inhibitors, there may be mentioned butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-methylpurine called olomucine. The subject of the present invention is also, as new industrial products, the synthetic intermediates of formulas (A), (B), (C), (D), (E), (F), (G) and ( H) as defined above and recalled below: NH 2 (A) (B) (C) S (D) (E) (F) S HS Rd N Rc i Rd N Rc (G) (H) as defined above wherein Ra, Rb, Rc and Rd are as defined above and R is t-butyl or phenyl. The following examples which are products of formula (I) illustrate the invention without however limiting it. Experimental Part The nomenclature of the compounds of this invention was performed with ACDLABS software version 10.0. The microwave oven used is a Biotage device, Initiator TM 2.0, 400W max, 2450 MHz. 1H NMR spectra at 400 MHz were carried out on BRUKER AVANCE DRX-400 spectrometer with chemical shifts (b in ppm) in dimethylsulfoxide-d6 solvent (DMSO-d6) referenced at 2.5 ppm at a temperature of 303K. Mass spectra (SM) were obtained either by Method A or Method B: Method A: WATERS UPLC-SQD Apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: ACQUITY BEH C18 1.7 μm - 2.1 x 50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 50 ° C; Flow rate: 1 ml / min; Gradient (2 min): 5 to 50% B in 0.8 min; 1.2 min: 100% B; 1.85 min: 100% B; 1.95: 5% B; Retention time = Tr (min). Method B: WATERS ZQ Apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: XBridge C18 2.5 μm - 3 x 50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 70 ° C; Flow rate: 0.9 ml / min; Gradient (7 min): from 5 to 100% of Ben5,3min, 5,5min: 100% of B; 6.3 min: 5% B; Retention time = Tr (min). Example 1 6- (Imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-25 amine Example 1a: 6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl The compound can be prepared in the following manner: In a sealed glass tube, 600 mg of 3-bromoimidazo [1,2-a] pyrimidine (commercial product), 1 mg. 0.5 g of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea, 840 mg of potassium carbonate and 12 ml of dimethylsulfoxide. The medium is heated by laying at 190 ° C for 12 minutes. After returning to a temperature of 20 ° C, the medium is poured into 200 ml of water and ice. The precipitate thus formed is isolated by filtration on sintered glass, rinsed 3 times with 10 ml of water and dried. The filtrate is extracted with 4 times 15 ml of dichloromethane and the combined organic extracts are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The evaporation residue and the previously isolated solid are chromatographed under argon pressure on silica gel (eluent dichloromethane / methanol 9/1). In this way 65 mg of 6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-amine are obtained in the form of a light brown solid.

Melting point> 260 ° C (Kefler). SM: method A; [M + H] +: m / z = 300; Tr = 0.41 min. 1H NMR (400MHz, DMSO-d6) δ ppm 7.12 (dd, J = 8.4, 2.2Hz, 1H) 7.19 (dd, J = 6.8, 4.2Hz, 1H) 7.23 (d, J = 8.4Hz, 1H NMR (CDCl3)? H) 7.51 (bs, 2H) 7.60 (d, J = 2.2Hz, 1H) 8.19 (s, 1H) 8.67 (dd, J = 4.2, 2.0Hz, 1H) 8.89 (dd, J = 6.8) , 2.0 Hz, 1H) Example 1b: 1- [2- (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea The compound can be prepared from following procedure: To a suspension of 900 mg of 2 - ({[2- (morpholin-4-yl) ethyl] carbamoyl} amino) -1,3-benzothiazol-6-yl thiocyanate in 35 ml of 20% ethanol. C., a solution of 11 mg of potassium dihydrogenphosphate in 2.3 ml of water followed by 1.1 g of DL-dithiothreitol is added. The white suspension is stirred for 18 hours under reflux. The reaction mixture is cooled to 20 ° C. and then 30 ml of water are added and the mixture is stirred for 15 minutes. The precipitate formed is drained and washed with large volumes of water. 633 mg of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea are thus obtained in the form of a white solid. SM: method B; [M + H] +: m / z = 339; [M-H] -: m / z = 337; Tr = 2.31 min. Example 1c: 2 - ({[2- (Morpholin-4-yl) ethyl] carbamoyl} amino) -1,3-benzothiazol-6-yl thiocyanate The compound can be prepared in the following manner: A solution of 1 of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate in 30 ml of tetrahydrofuran was added 0.44 ml of 2-morpholin-4-ylethanamine at 20 ° C. The reaction medium is stirred at 20 ° C. for 24 hours and then concentrated by evaporation under reduced pressure. The residue obtained is chromatographed on a Merck 70g cartridge (solid deposit, elution with a dichloromethane gradient and then 90/10 dichloromethane / methanol). 902 mg of 2 - ({[2- (morpholin-4-yl) ethyl] carbamoyl} amino) -1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a colorless foam. SM: method A; [M + H] +: m / z = 364; Tr = 0.99 min. Example 1d: Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate The compound can be prepared as follows: To a solution of 2.5 g of 2-amino-1,3 thiocyanate benzothiazol-6-yl (commercial product) in 94 ml of tetrahydrofuran is added at 20 ° C, 7.5 g of phenyl chlorocarbonate then 4.05 g of sodium hydrogen carbonate and 9.4 ml of water . The reaction medium is stirred at 20 ° C. for 20 hours and then extracted twice with 150 ml of ethyl acetate. The organic phases are combined and then washed 3 times with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in 50 ml of water and then filtered off and dried under vacuum at 20 ° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate are thus obtained in the form of a pale yellow solid. SM: method B; [M + H] +: m / z = 328; [M-H] -: m / z = 326, Tr = 3.89 min.

The 6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-amine compound (Example 1 and 1a) can also be obtained in the following manner: A suspension of 310 mg of 4- (Imidazo [1,2-a] pyrimidin-3-ylsulfanyl) aniline, 25 ml of acetic acid and 500 mg of potassium thiocyanate are stirred until solubilization. 66 μl of bromine in solution in 3 ml of acetic acid are then added dropwise. The reaction medium is stirred at a temperature of 20 ° C for 48 hours and then poured into 70 ml of ice water. The pH is brought to about 11 by adding 10N sodium hydroxide. The precipitate formed is filtered, washed with water, drained and dried. There is thus obtained 242 mg of 6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-amine as a yellow solid. Example 1: 4- (Imidazo [1,2-a] pyrimidin-3-ylsulfanyl) aniline The compound can be prepared in the following manner: A solution of 770 mg of N- [4- (imidazo [1,2-a] ] Pyrimidin-3-ylsulfanyl) phenyl] acetamide (770 mg, 2.7 mmol), 5.2 ml of hydrochloric acid (37% by volume) and 60 ml of ethanol were refluxed for 8 hours. After returning to ambient temperature, the medium is concentrated to dryness by evaporation under reduced pressure and the residue obtained is taken up with a saturated aqueous solution of sodium hydrogen carbonate and extracted with 3 times 50 ml of dichloromethane. The combined organic extracts are dried, filtered and concentrated to dryness under reduced pressure. The evaporation residue is chromatographed under argon pressure on silica gel (eluent: 94/6 dichloromethane / methanol). 480 mg of 4- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) aniline are thus obtained in the form of a yellow solid.

SM: method A; [M + H] +: m / z = 243; Tr = 0.35 min. Example 1f: N- [4- (Imidazo [1,2-a] pyrimidin-3-ylsulfanyl) phenyl] acetamide The compound can be prepared in the following manner: 1.42 g of a glass tube is sealed 3-bromoimidazo [1,2-a] pyrimidine (commercial product), 1.18 g of N- (4-sulfanylphenyl) acetamide (commercial product), 1.95 g of potassium carbonate and 15 ml of dimethylsulfoxide. The medium is heated by laying at 180 ° C for 12 minutes. After returning to a temperature of 20 ° C, the medium is poured into 250 ml of water and ice. The precipitate thus formed is filtered, washed with 3 times 70 ml of water and dried and the filtrate is extracted with 150 ml of dichloromethane. The combined organic extracts are washed with 2 times 30 ml of water, dried over magnesium sulphate, filtered and concentrated to dryness by evaporation under reduced pressure. The previously isolated precipitate and the extract are combined to be chromatographed on silica gel under argon pressure (eluent dichloromethane / methanol 9/1). There is thus obtained 780 mg of N- [4- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) phenyl] acetamide as a beige solid. SM: method A; [M + H] +: m / z = 285; [MH]: m / z = 283, Tr = 1.07 min Example 2: N- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2- The compound can be prepared in the following manner: To a solution of 135 mg of 6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-amine and 5 ml of pyridine is added dropwise 45 μl of cyclopropanecarbonyl chloride The reaction medium is stirred at a temperature of 20 ° C. for 16 hours and then concentrated to dryness under reduced pressure The evaporation residue is chromatographed under pressure The resulting solid is triturated with ethyl acetate, filtered and dried to give 2820 mg of N- [6- (imidazo) [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide as a yellow solid, mp = 258 ° C (Kbfler) MS: Method B; M + H] +: m / z = 368, [MH] -: m / z = 366, Tr = 3.23 min.

1H NMR (400MHz, DMSO-d6) δ ppm 0.86 - 0.96 (m, 4H) 1.91 - 2.00 (m, 1H) 7.15 - 7.25 (m, 2H) 7.61 (d, J = 8.3Hz, 1H) ) 7.82 (d, J = 2.0Hz, 1H) 8.23 (s, 1H) 8.69 (dd, J = 4.2, 2.0Hz, 1H) 8.87 (dd, J = 6.8, 2.0Hz, 1H) 12.54 - 12.68 (m, spread 1 H) Example 3: N- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] acetamide The compound can be prepared from following procedure: A solution of 73 mg of 6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-amine, 2 ml of acetic anhydride and 2 ml of pyridine is refluxed for 8 hours. After concentration of the reaction medium to dryness by evaporation under reduced pressure, the residue obtained is chromatographed under argon pressure on silica gel (eluent dichloromethane / methanol 95/5). The solid obtained is triturated in 2 ml of isopropanol. The solid obtained is filtered, washed twice with 1 ml of isopropanol, 3 times with 3 ml of diisopropyl ether and dried. N- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] acetamide (51 mg) is thereby obtained in the form of a yellow solid. Melting point> 260 ° C (Kofler). SM: method A; [M + H] +: m / z = 342; [M-H] -: m / z = 340; Tr = 0.58 min.

1H NMR (400MHz, DMSO-d6) δ ppm2.17 (s, 3H) 7.17-7.21 (m, 2H) 7.62 (d, J = 8.6Hz, 1H) 7.83 (d, J = 2.0Hz, m.p. 1H) 8.23 (s, 1H) 8.69 (dd, J = 4.2, 2.0Hz, 1H) 8.86 (dd, J = 6.7, 2.0Hz, 1H) 12.25 - 12.35 (m, spread, 1H) Example 4 1- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] -3- [2- (morpholin-4-yl) ethyl] The compound can be prepared in the following manner: A mixture of 171 mg of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea, 5 ml ethanol, 1 mg potassium dihydrogenphosphate, 0.1 ml water, 100 mg 3-bromoimidazo [1,2-a] pyrimidine (commercial product) and 0.1 ml of triethylamine is refluxed for 16 hours. The precipitate which appeared was removed by filtration on sintered glass, washed with ethanol and the filtrate was concentrated to dryness under reduced pressure. The isolated residue is chromatographed under argon pressure on silica gel (eluent dichloromethane / methanol 9/1). 22 mg of 1- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] -3- [2- (morpholin-4-yl) are thus obtained. ethyl] urea as a white solid. Melting point> 260 ° C (Kofler).

SM: method A; [M + H] +: m / z = 456; [M + H-C 7 H 12 N 2 O 2] +: m / z = 300; Tr = 0.45 min. 1H NMR (400MHz, DMSO-d6) δ ppm 2.33 - 2.45 (m, 6H) 3.25 (partially masked m, 2H) 3.57 (m, 4H) 6.77 (bcm 1H) 7.13 - 7.21 (m, 2H) 7.48 (broad d, J = 8.8 Hz, 1H) 7.78 (bs, 1H) 8.22 (s, 1H) 8.67 (dd, J = 4.5, 2.1Hz, 1H) 8.88 (dd, J) = 6.7, 2.1 Hz, 1H) 10.86 (extended m, 1H). Example 5: Pharmaceutical composition Tablets having the following formula were prepared: Product of Example 1 0.2 g Excipient for a tablet finished at 1 g (detail of excipient: lactose, talc, starch, magnesium stearate ). Example 1 is taken as an example of a pharmaceutical preparation, this preparation can be carried out if desired with other products examples in the present application.

Pharmacological Part: Experimental Protocols I) Expression and Purification of MET, Cytoplasmic Domain Baculovirus Expression: Recombinant His-Tev-MET (956-1390) DNA in pFastBac (Invitrogen) is Transfected into Insect Cells and After Several Steps viral amplification, the final baculovirus stock is tested for expression of the protein of interest. After infection for 72 h at 27 ° C with the recombinant virus, the SF21 cell cultures are harvested by centrifugation and the cell pellets are stored at -80 ° C. Purification: The cell pellets are resuspended in lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCl, 10% Glycerol, 15 mM TECP 1] + Roche Diagnostics protease inhibitor cocktail without EDTA ref 1873580), stirred at 4 ° C until homogeneous, then mechanically lysed using a Dounce type apparatus. After centrifugation, the lysis supernatant is incubated for 2 hours at 4 ° C. with Nickel Chelate resin (His-Trap 6 Fast FlowTM, GE HealthCare). After washing with 20 volumes of Tp A, the suspension is packaged in a column, and the proteins are eluted by a gradient of buffer B (TpA + 290 mM imidazole). The fractions containing the protein of interest in view of the electrophoretic analysis (SDS PAGE) are pooled, concentrated by ultrafiltration (cut-off 10kDa) and injected on an exclusion chromatography column (Superdex TM 200, GE HealthCare). balanced in buffer A. After enzymatic cleavage of the Histidine tag, the protein is re-injected onto a new IMAC Nickel Chelate chromatography column (His-Trap 6 Fast FlowTM, GE HealthCare) equilibrated in Buffer A. The fractions eluted by a gradient of buffer B and containing the protein after electrophoresis (SDS PAGE), are finally pooled and stored at -80 ° C. For the production of autophosphorylated protein, the previous fractions are incubated for 1 h at room temperature after addition of 2mM ATP, 2mM MgCl 2, and 4mM Na3VO4. After stopping the reaction with 5mM EDTA, the reaction mixture is injected onto a HiPrep desalting column (GE HealthCare) previously equilibrated with 4mM A + Na3VO4 buffer, the fractions containing the protein of interest (SDS PAGE analysis) are pooled. and stored at -80 ° C. The level of phosphorylation is verified by mass spectrometry (LC-MS), and by peptide mapping. II) Tests A and BA) Test A: HTRF MET assay in 96-well format In a final volume of 50 μl of enzymatic reaction, final 5nM MET is incubated in the presence of the molecule to be tested (for a final concentration range of 0.17 nM 10 NM, DMSO 3% final) in 10 mM MOPS buffer pH 7.4, 1 mM DTT, 0.01% Tween 20. The reaction is initiated by the substrate solution to obtain the final concentrations of 1 μg / ml poly- (GAT), 10 μM ATP and 5 μM MgCl 2. After a 10 min incubation at room temperature, the reaction is stopped by a 30 μl mix to obtain a final solution of 50 mM Hepes pH 7.5, 500 mM potassium fluoride, 0.1% BSA and 133 mM EDTA in the presence of 80 μg Streptavidin. 61SAXLB Cis-Bio Int. and 18ng anti-Phosphotyrosine Mab PT66-Europium Cryptate per well. After 2 hours incubation at room temperature, the reading is made at 2 wavelengths 620 nm and 665 nm on a reader for the TRACE / HTRF technique and the% inhibition is calculated according to the 665/620 ratios. The results obtained by this test A for the products of formula (I) as examples in the experimental part are such that IC50 is less than 500 nm and in particular 100 nm. B) Test B: Inhibition of MET autophosphorylation; ELISA technique (pppY1230,1234,1235) a) Cell lysates: Inoculate MKN45 cells in 96-well plate (BD polylysine cell coat) at 20,000 cells / well under 200 μl in RPMI + 10% FCS + 1% L-glutamine medium. . Allow 24 hours to adhere to the incubator. The cells are treated the day after seeding with the products at 6 concentrations in duplicate for 1 h. At least 3 control wells are treated with the same amount of final DMSO. Dilution of products: Stock at 10mM in pure DMSO - Range of 10mM to 30pM with a step of 3 in pure DMSO - Dilutions intermediate to 1/50 in culture medium then 10p1 sample added directly to the cells (200p1): range final from 10000 to 30nM. At the end of the incubation, gently remove the supernatant and rinse with 200 μl of PBS. Then put 100 μL of lysis buffer directly into the wells on the ice and incubate at 4 ° C for 30 minutes. Lysis buffer: 10mM Tris, pH 7.4 HCl, 100mM NaCl, 1mM EDTA, 1mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 20mM NaF, 2mM Na3VO4, 1mM PMSF and cocktail anti proteases. The 100 μl lysates are transferred to a V-bottom polypropylene plate and the ELISA is carried out immediately or the plate is frozen at -80 ° C. b) ELISA PhosphoMET BioSource Kit KHO0281 In each well of the kit plate, add 70 μl of 30 μl dilution buffer of cell lysate kit or 30 μl of lysis buffer for the blanks. Incubate for 2h with gentle shaking at room temperature. Rinse the wells 4 times with 400 μl of wash buffer from the kit. Incubate with 100 μl of anti-phospho MET antibody for 1 hr at room temperature.

Rinse the wells 4 times with 400 μl of wash buffer from the kit. Incubate with 100 μl of HRP Anti-Rabbit Antibody for 30 minutes at room temperature (except for chromogen wells alone). Rinse the wells 4 times with 400 μl of kit wash buffer. Put 100 μl of chromogen and incubate 30 minutes in the dark at room temperature.

Stop the reaction with 100 μl of stop solution. Read without delay at 450nM 0.1 seconds at Wallac Victor flat reader. C) Test C: Measurement of Cell Proliferation by 14C-Thymidine Pulse The cells are seeded in Cytostar 96-well plates under 180 μl for 4 hours at 37 ° C. and 5% CO 2: the HCT116 cells at the rate of 2500 cells per well in DMEM medium + 10% fetal calf serum + 1% L-Glutamine and MKN45 cells at 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine.

After these 4 hours of incubation, the products are added under 10 μl in 20-fold concentrated solution according to the dilution method cited for ELISA. The products are tested at 10 duplicate concentrations of 10000 nM to 0.3 nM with a 3 step. After 72 hours of treatment, add 10 μl of 14 C-thymidine at 10 μCi / ml to obtain 0.1 μCi per well. The incorporation of 14 C-thymidine is measured on a Micro-Beta (Perkin-Elmer) after 24 hours of pulse and 96 hours of treatment. All stages of the test are automated on BIOMEK 2000 or TECAN stations. The results obtained by this test B for the products of formula (I), for example in the experimental part, are such that IC50 is less than 10 microm and especially 1 microm. The results obtained for the exemplary products in the experimental part are given in the table of pharmacological results below, as follows: for test A, the sign + corresponds to less than 500 nM and the sign corresponds to less than 100 nM. for test B the sign + corresponds to greater than 500nM and the sign corresponds to less than 100nM. ++ ++ for the C test the + sign corresponds to less than 10 microM and the sign ++ corresponds to less than 1 microM. Table of pharmacological results: example Test A Test B Test C 1 ++ + ++ 2 ++ ++ ++ 3 ++ ++ ++ 4 ++ ++ ++ 10 15 20 25

Claims (21)

1) Products of formula (I): ## STR2 ## in which: Ra represents a hydrogen atom, a halogen atom, an aryl radical or a heteroaryl radical, these aryl and heteroaryl radicals being optionally substituted as indicated below; Rb represents a hydrogen atom, an Rc radical, -COORc, -CO-Rc or a -CONRcRd radical; with Rc represents an alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl radical, all these radicals being optionally substituted as indicated below; moreover, when Rc represents cycloalkyl, then this cycloalkyl radical is optionally substituted by one or more radicals chosen from heterocycloalkyl, aryl and heteroaryl themselves optionally substituted as indicated below; moreover, when Rc represents alkyl, then this alkyl radical is optionally substituted by one or more heterocycloalkyls, themselves optionally substituted as indicated below; Rd represents a hydrogen atom or an alkyl or cycloalkyl radical; all the radicals defined above, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, being optionally substituted with one or more radicals chosen from halogen atoms, and hydroxyl, alkoxy, CN, CF3, -NR1 R2, -000H radicals; , -COOalk, -CONR1 R2 and -NRICOR2; the alkyl radicals being furthermore optionally substituted with an aryl or heteroaryl radical, themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy and NR3R4 radicals; the cycloalkyl, heterocycloalkyl, aryl or heteroaryl radicals being furthermore optionally substituted with an alkyl radical, itself optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy and NR3R4 radicals; NR1 R2 being such that: either, R1 and R2 being identical or different, one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a radical cycloalkyl or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted; or R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including 1 any NH it contains being optionally substituted; NR3R4 being such that: either, R3 and R4 being identical or different, one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a cycloalkyl radical; or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heterocycloalkyl, heteroaryl or phenyl radicals, themselves optionally substituted, or R 3 and R 4 form, with the nitrogen atom to which they are bonded, a radical cyclic ring containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the cyclic radicals that can be formed by R 1 and R 2 or R 3 and R 4 respectively with the nitrogen atom to which they are bonded, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, oxo radicals, alkoxy, NH2; NHalk, N (alk) 2, and the alkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter radicals the alkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals selected from the group consisting of halogen and hydroxyl, alkyl and alkoxy radicals having 1 to 4 carbon atoms, NH 2; NHalk and N (alk) 2; all the above alkyl (alk) and alkoxy radicals containing from 1 to 6 carbon atoms, R1 and R2 identical or different having the meanings indicated above, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 2) Products of formula (I) as defined in claim 1 wherein: Ra represents a hydrogen atom; a halogen atom; or an aryl or heteroaryl radical, these aryl and heteroaryl radicals being optionally substituted as indicated below; Rb represents a hydrogen atom, a -CO-Rc radical or a -CONRcRd radical; with Rc represents an alkyl radical or a cycloalkyl radical, both optionally substituted with one or more radicals chosen from hydroxyl, alkoxy, NR1 R2, heterocycloalkyl, aryl and heteroaryl radicals themselves optionally substituted as indicated below; Rd represents a hydrogen atom or an alkyl radical; all the radicals defined above, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, being optionally substituted with one or more radicals chosen from halogen atoms, and hydroxyl, alkoxy, -NR 1 R 2, -000H, -COOalk and -CONR1 R2, NR1 R2 being such that: either, R1 and R2 being identical or different, one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents an atom of hydrogen, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted; or R1 and R2 together with the nitrogen atom to which they are bound cyclic unradical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the any NH that it contains being optionally substituted; NR3R4 being such that: either, R3 and R4 being identical or different, one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a cycloalkyl radical; or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heterocycloalkyl, heteroaryl or phenyl radicals, themselves optionally substituted, or R 3 and R 4 form, with the nitrogen atom to which they are bonded, a radical cyclic ring containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the cyclic radicals that can be formed by R 1 and R 2 or R 3 and R 4 respectively with the nitrogen atom to which they are bonded, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, alkoxy radicals; and the alkyl, phenyl and CH 2 -phenyl radicals, in which the alkyl or phenyl radicals are themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals. NH2, NHalk and N (alk) 2; all the above-mentioned alkyl (alk) or alkoxy radicals containing from 1 to 6 carbon atoms, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I). 3) Products of formula (I) as defined in claim 1 or 2 wherein: Ra represents a hydrogen atom; a halogen atom; or an optionally substituted phenyl radical as indicated below; Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-N radical RcRd; with Rc represents an alkyl or cycloalkyl radical, both optionally substituted by one or more radicals chosen from hydroxyl, alkoxy, NR1R2 and phenyl radicals, itself optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl radicals; alkoxy, alkyl, NH2, NHalk and N (alk) 2; Rd represents a hydrogen atom or an alkyl radical; NR 1 R 2 is such that either, R 1 and R 2 being identical or different, one of R 1 and R 2 represents a hydrogen atom or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4 or phenyl radicals, themselves optionally substituted; or R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 4 to 7 members and optionally another heteroatom selected from O, S, N and NH, this radical including the optional NH that it contains being optionally substituted; NR3R4 being such that either R3 and R4 are identical or different, represent a hydrogen atom or an alkyl radical optionally substituted by one or more identical or different radicals chosen from hydroxyl or alkoxy radicals, or R3 and R4 form with the atom of nitrogen to which they are attached a cyclic radical containing from 4 to 7 members and optionally another heteroatom selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the cyclic radicals that can be formed by R 1 and R 2 or R 3 and R 4 respectively with the nitrogen atom to which they are bonded, being optionally substituted with one or more identical or different radicals as defined in any one of Claims 1 or 2; all the above alkyl (alk) or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 4) Products of formula (I) as defined in any one of the preceding claims wherein: Ra represents a hydrogen atom; a halogen atom; or a phenyl radical optionally substituted by a halogen atom; Rb represents a hydrogen atom, a -CO-Rc radical or a -CONRcRd radical; with Rc represents an alkyl or cycloalkyl radical optionally substituted by one or more radicals chosen from hydroxyl, alkoxy and NR1 R2 radicals; Rd represents a hydrogen atom; NR1R2 being such that either R1 and R2, which may be identical or different, represent a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy and NH2 radicals; NHalk and N (alk) 2 or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 4 to 7 members and optionally another heteroatom chosen from O, S, N and NH, optionally substituted by an alkyl, phenyl or -CH 2 -phenyl radical, these last 25 radicals themselves being optionally substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals. NH2, NHalk and N (alk) 2; all the above alkyl (alk) or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I). 5) Products of formula (I) as defined in any one of the preceding claims wherein: Ra represents a hydrogen atom; Rb represents a hydrogen atom, a CO-Rc radical or a radical -COù10 NRcRd; with Rc represents a cyclopropyl radical or an alkyl radical optionally substituted by an alkoxy radical or NR1 R2; Rd represents a hydrogen atom, NR 1 R 2 being such that either R 1 and R 2 are identical or different, represent a hydrogen atom or an alkyl radical, or R 1 and R 2 form, with the nitrogen atom to which they are bonded, a morpholinyl radical; ; the above alkyl or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral acids and organic or with the inorganic and organic bases of said products of formula (I). 6) Products of formula (I) as defined in any one of the other claims, having the following formulas: 6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazole 2-Amino-N- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide 5-N- [6- (imidazo [1,2- a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] acetamide - 1- [6- (imidazo [1,2-a] pyrimidin-3-ylsulfanyl) -1,3-benzothiazol-2- yl] -3- [2- (morpholin-4-yl) ethyl] ure, as well as addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I). 7) Process for preparing the products of formula (I) as defined in any one of the other claims according to Scheme 1 as defined below. Scheme 1: Coupling N NH NH 2 HS + (C) cyclization (A) (B) (I) wherein the substituents Ra and Rb have the meanings indicated in any one of Claims 1 to 5. 8) Process for the preparation of the products of formula (I) as defined in any one of the other claims according to Scheme 2 as defined below. Scheme 2: Rc (Rd) NH Rd N (G) Rc coupling NH2 reduction coupling (A) Rd N Rc HS (I) Rb = CONHRc in which the substituents Ra, Rc and Rd have the meanings indicated in any one of claims 1 to 5. 9) As medicaments, the products of formula (I) as defined in any one of claims 1 to 6, as well as the addition salts with inorganic and organic acids or with the mineral and organic bases pharmaceutically acceptable said products of formula (I). 10) As medicaments, the products of formula (I) as defined in claim 6, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I ). 11) Pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier. 12) Use of the products of formula (I) as defined in any one of claims 1 to 6, or pharmaceutically acceptable salts of these products for the preparation of a medicament for inhibiting the activity of the MET protein kinase and its mutant forms for antiproliferative and anti-metastatic treatment, especially in oncology. 13) The use as defined in claim 12, wherein the protein kinase is in a cell culture. 14) Use of a product of formula (I) as defined in any one of claims 1 to 6, for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: disorders of blood vessel proliferation, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers. 15) Use of a product of formula (I) as defined in any one of claims 1 to 6 for the preparation of a medicament for the treatment of cancers. 16) Use according to claim 15 for the treatment of solid or liquid tumors. 17) Use according to claim 15 or 16 for the treatment of cancers resistant to cytotoxic agents. 18) Use according to one or more of claims 15 or 16 for the treatment of primary tumors and / or metastases especially in gastric, hepatic, renal, ovarian, colon, prostate, lung cancers (NSCLC and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain, larynx, lymphatic system, cancer bones and pancreas. 19) Use of the products of formula (I) as defined in claims 1 to 6, for the preparation of medicaments for the chemotherapy of cancers. 20) Use of the products of formula (I) as defined in claims 1 to 6, for the preparation of medicaments for cancer chemotherapy alone or in combination. 21) As new industrial products, the synthetic intermediates of formulas (A), (B), (C), (D), (E), (F), (G) and (H) as defined in Claims 7 and 8 above and recalled below: H2 (A) (B) (C) Rc i N% o 0 R o R (D) (E) (F) HS Rd N Rc (G) (H) ) in which Ra, Rb, Rc and Rd are as defined in any one of claims 1 to 5 and R is t-butyl or phenyl.